18.1 Introduction

Anaplastic thyroid cancer (ATC) is a rare thyroid cancer characterized by an aggressive disease course and a high mortality rate. ^{1 , 2} Commonly, patients will present with a rapidly growing neck mass and symptoms related to invasion or compression of structures within the neck. At diagnosis, many patients will already have widespread metastatic disease. ³ Clinical decision making in a majority of cases is directed toward palliation. This chapter discusses treatment approaches for patients with ATC and reviews the limited role for surgical intervention.

18.2 The Spectrum of Thyroid Cancers

Well-differentiated thyroid cancers arising from follicular thyroid cells are associated with excellent disease-specific survival outcomes. Localized tumors are managed with thyroidectomy and, in select cases, lymph node dissection and/or adjuvant radioactive iodine therapy. ⁴ Even patients with metastatic differentiated thyroid cancer can experience prolonged survival. ⁵ This is in stark contrast to patients with ATC, the course of which is as aggressive as any other human cancer. ATCs are composed of undifferentiated cells that do not have the ability to take up radioactive iodine. These tumors are highly fludeoxyglucose (FDG)-avid on positron emission tomography (PET). ⁶ Characteristic histological findings include necrosis, local invasiveness, large nuclei, and frequent mitotic figures (Fig. 18.1). ⁷ The spindle cells found in ATC can easily be mistaken for other spindle cell neoplasms, including sarcoma. A pathologist experienced with ATC is critical in cases of diagnostic uncertainty. This is because histopathologic diagnoses (particularly in the setting of a metastatic biopsy) can be complicated by a loss of typical differentiated thyroid-specific immunohistochemistry (IHC) markers that identify a thyroid origin. Accordingly, given the highly undifferentiated nature of these tumors, pathological diagnosis of ATC often requires knowledge of the location of the tumor biopsy site and careful consideration of the patient’s clinical history.

Histological evidence suggests that some anaplastic cancers may originate from antecedent thyroid disease. Both goiter and well-differentiated thyroid cancers can be seen adjacent to anaplastic cells in resected specimens. Molecular analyses demonstrate that mutually exclusive genomic changes in mitogen-activated protein kinase (MAPK) pathway genes (RAS, BRAF, RET/PTC fusions) contribute to thyroid cancer pathogenesis. Additional genetic changes in DNA repair genes (p53) and the telomerase promoter may trigger genomic instability and cell immortalization that is required for transformation to an undifferentiated tumor. ^{8 , 9} Given the high incidence of clinical and subclinical thyroid cancers in the general population, clearly this transformation occurs at a very low rate. The incidence of ATC in the United States has been stable over time, ranging between 0.1 and 0.2 per 100,000 persons, accounting for fewer than 1% of thyroid cancer diagnoses. ¹⁰

ATCs are responsible for a large percentage of deaths related to thyroid cancer in the United States. Although few large series of patients exist, ATC is thought to have one of the shortest median survival rates of all cancers, ranging from 3 to 5 months. ¹¹ A majority of patients will have metastatic disease at presentation (Fig. 18.2). In addition, many patients will have large, rapidly growing neck tumors that can compress the airway. Surgical series frequently report patients who underwent thyroidectomy and received an incidental diagnosis of ATC at the time of pathological analysis. These are uncommon entities and are not representative of the vast majority of patients presenting with clinically evident ATC. Thus the outcomes of these single-institutional experiences should be interpreted cautiously. In the majority of cases, ATC is unfortunately a disease rarely able to be effectively treated with surgical resection.

18.3 Initial Evaluation of a Rapidly Expanding Neck Mass

Patients presenting with an enlarging neck mass require a histological diagnosis and imaging of the head and neck (Fig. 18.3). Percutaneous core or fine-needle biopsy under ultrasound guidance provides excellent visualization and can confirm tumor sampling while avoiding vital structures. Open biopsy is rarely performed given the success of percutaneous techniques, but it is occasionally needed. Once the diagnosis has been established, staging workup should include laboratory testing and contrast-enhanced imaging of the head and neck, including brain magnetic resonance imaging (MRI) with full-body FDG-PET (Fig. 18.4 and Fig. 18.5). ¹²

Thyroid function tests, blood counts, and full chemistry panels should be checked in anticipation of multimodality therapy (surgery, chemotherapy, and radiation). Laryngoscopy to assess vocal cord mobility should be performed in all patients. Locally unresectable tumors invade and surround the carotid artery, prevertebral fascia, mediastinal structures, trachea, larynx, or esophagus. ¹³ For localized tumors thyroidectomy with lymph node dissection is reasonable, but this is an extremely uncommon presentation of ATC. ¹² Tumors that extensively invade local structures are not appropriate for surgical resection. En bloc resection would often require extensive surgery with laryngectomy, pharyngectomy, and esophagectomy, and is unlikely to be of value, given the high likelihood of residual gross disease even after extensive resection together with the high likelihood of the development of distant metastases within a short time interval. For patients with metastatic disease identified on cross-sectional imaging/PET it should be noted that this may represent a more well-differentiated component of the tumor. High FDG avidity suggests ATC, but if there is suspicion of low-grade metastatic disease, serum thyroglobulin levels can be helpful.

Patients with distant metastatic disease should be referred for systemic therapy or multimodality treatments that include radiation. ¹⁴ Data to suggest one particular treatment approach over another are lacking, and the authors suggest referral to a multidisciplinary group with experience in treating ATC. Enrollment in a clinical trial is optimal. Timely coordination of care across experienced specialists is critical to providing optimal palliative care.